Chronic clomipramine alters presynaptic 5-HT1B and postsynaptic 5-HT1A receptor sensitivity in rat hypothalamus and hippocampus, respectively

Clomipramine is a tricyclic antidepressant drug with a high affinity for th e serotonin (5-HT) uptake site or transporter. Electrophysiological experim ents have provided evidence that repeated administration of clomipramine in duces an increase in the sensitivity of postsynaptic 5-HT1A receptors in th e hippocampus. We have studied the effects of clomipramine, administered to rats at a dose of 10 mg/kg/day for 28 days by osmotic minipumps, on presyn aptic 5-HT1A and 5-HT1B autoreceptors in the hypothalamus, and on postsynap tic 5-HT1A receptors in the hippocampus, by using in vivo microdialysis to measure 5-HT and cyclic adenosine monophosphate (cAMP) levels. Postsynaptic 5-HT1A receptor sensitivity in the hypothalamus was determined by means of a neuroendocrine challenge procedure. Although the sensitivity of presynap tic 5-HT1A autoreceptors, as measured by the effect of a subcutaneous (s.c. ) injection of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.2 mg/kg or 50 mu g/kg) to reduce 5-HT levels, did not change, there was a reductio n in sensitivity of presynaptic 5-HT1B receptors, as measured by the effect of an injection of the 5-HT1B/1D antagonist GR 127935 (5 mg/kg, s.c.) to i ncrease 5-HT levels. This effect probably accounted for the increase in bas al 5 HT levels observed in the hypothalamus after chronic clomipramine admi nistration. Postsynaptic 5-HT,, receptor sensitivity in the hippocampus, me asured by the effect of 8-OH-DPAT to increase cAMP levels in the dialysate, was increased after chronic clomipramine. Animals that had received daily intraperitoneal injections of 10 mg/kg clomipramine for 28 days did not sho w a change in postsynaptic 5-HT1A receptor sensitivity in the hypothalamus as measured by the ability of 8-OH-DPAT (50 mu g/kg, s.c.) to stimulate sec retion of corticosterone. Taken together with the results of previous exper iments involving the cerebral cortex, these in vivo results show that chron ic clomipramine exerts effects on both pre- and postsynaptic serotonin rece ptors. but that these effects are highly region-specific. (C) 2000 Elsevier Science Ltd. All rights reserved.